Supplementation Materials

Supplementation materials:

Title: Hyponatremia and Osteoporosis: Reappraisal of a Novel Association

Journal Name: Osteoporosis International

Authors:

Farsad Afshinnia, MD: Division of nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Baskaran Sundaram, MBBS: Division of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania

Robert J Ackermann, BS, CNMT: Department of Nuclear Medicine/ Radiology, University of Michigan, Ann Arbor, Michigan

Ka Kit Wong, MBBS: Department of Nuclear Medicine/Radiology, University of Michigan, Ann Arbor, Michigan, and VA Ann Arbor Healthcare System, Ann Arbor, Michigan

Corresponding Author: Farsad Afshinnia MD Email: [email protected]

1 Supplement Table 1: List of comorbidities and their corresponding ICD9 codes used to search for identification of the known comorbidities

Comorbidities ICD9 codes Anorexia nervosa 307.1 Bulimia 307.51 Inflammatory arthridites 714, 714.8, 714.81, 714.89, 714.9, 720, 720.8, 720.81, 720.89 Solid organ E878, V42, V42.0, V42.1, V42.2, V42.3, V42.4, V42.6, V42.7, V42.8, transplantation V42.9 Malabsorption 579, 579.8, 579.9 Osteomalacia 268.2 Endometriosis 617, 617.0, 617.1, 617.2, 617.3, 617.4, 617.5, 617.6, 617.7, 617.8, 617.9 Acromegaly 253.0 Hyperparathyroidism 252.0, 252.01, 252.02, 252.08, 588.81 Hyperthyroidism 242, 242.1, 242.3, 242.9 Cushing syndrome 255.0 Chronic alcoholism 303, 303.9 Cirrhosis 571, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.6, 571.8, 571.9 Multiple myeloma 203.0 Bariatric surgery V45.86, V45.3, V45.89 Hip fracture 733.14, 733.96, 820.0, 820.1, 820.2, 820.3 Spine fracture 733.13, 805, 806

2 Supplement Table 2: List of class of medications searched in the clinical records of each patient

Medication class Including Calcium supplementation Any form including Calcium Chloride, Calcium Carbonate, Calcium Acetate, Calcium Citrate Vitamin D Any form including synthetic analogues Bisphosphonates Alendronate, Etidronate, Ibandronate, Pamidronate, Risedronate, Zoledronic Acid Thiazide diuretics Hydrochlorothiazide, Chlorthalidone, Indapamide, Metolazone, Zaroxolyn, Methyclothiazide Loop diuretics Furosemide (Lasix), Bumetanide (Bumex), Torsemide (Demadex), Edecrin Steroids Cortisol, Cortisone, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone Anti-consultants Paraldehyde, Phenobarbital, Diazepam, Carbamazapine, Oxcarbazepine, Valproic acid, Divalproex, Topiramate, Gabapentin, Pregabalin, Phenytoin, Fosphenytoin, Levetiracetam, Ethosuximide, Acetazolamide, Lamotrigine Anti-depressants Citalopram (Celexa), Escitalopram (Lexapro, Cipralex), Paroxetine (Paxil, Seroxat), Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft, Lustral), Mirtazapine (Remeron, Avanza, Zispin), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Levomilnacipran (Fetzima), Etoperidone (Axiomin, Etonin), Nefazodone (Serzone, Nefadar), Trazodone (Desyrel), Vilazodone (Viibryd), Vortioxetine (Brintellix), Bupropion (Wellbutrin, Zyban), Amitriptyline (Elavil, Endep), Amoxapine (Asendin), Clomipramine (Anafranil), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Trimipramine (Surmontil), Desipramine (Norpramin), Nortriptyline (Pamelor, Aventyl, Noritren), Protriptyline (Vivactil), Tianeptine (Stablon, Coaxil, Tatinol), Amineptine (Survector), Opipramol (Insidon, Pramolan, Ensidon, Oprimol), Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Eldepryl, Emsam), Tranylcypromine (Parnate), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol) Opiates Codeine, Morphine, Hydrocodone, Hydromorphone, Oxycodone, Fentanyl, Propoxyphene, Methadone, Diphenoxylate, Loperamide Androgen deprivation therapy Leuprolide, Goserelin, Triptorelin, Histrelin, Degarelix, Flutamide, Bicalutamide, Nilutamide Aromatase inhibitor therapy Aminoglutethimide, Testolactone (Teslac), Anastrozole (Arimidex), Letrozole (Femara), Exemestane (Aromasin), Vorozole (Rivizor), Formestane (Lentaron), Fadrozole (Afema), 4-Hydroxyandrostenedione, 1,4,6-Androstatrien-3,17-dione (ATD), 4-Androstene-3,6,17-trione ("6-OXO"), Resveratrol, Nicotine, Myosmine, Zinc, Catechin, Chalcones, Apigenin, Eriodictyol, Isoliquiritigenin, Mangostin

3 4 Supplement Table 3: Odds ratio of osteoporosis by age and sodium categories in various models

Lumbar (Model 1): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) <0.001 ≤135 35 (24.0%) 2.101 1.419 to 3.11 <0.001 136-140 498 (12.5%) 0.948 0.828 to 1.085 0.439 141-145 469 (13.0%) 1 (Reference) >145 3 (12.0%) 0.909 0.271 to 3.048 0.877

Age 55-67 (N=8680) ≤135 51 (26.8%) 1.53 1.102 to 2.124 0.011 136-140 588 (17.8%) 0.905 0.808 to 1.013 0.082 141-145 989 (19.3%) 1 (Reference) >145 23 (28.8%) 1.682 1.031 to 2.743 0.037

Age >67 (N=8341) ≤135 114 (31.1%) 1.294 1.028 to 1.63 0.028 136-140 863 (25.9%) 1.005 0.908 to 1.113 0.925 141-145 1185 (25.8%) 1 (Reference) >145 12 (21.8%) 0.802 0.421 to 1.525 0.501

Lumbar (Model 2): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) <0.001 ≤135 35 (24.0%) 1.989 1.339 to 2.957 0.001 136-140 498 (12.5%) 0.951 0.83 to 1.09 0.472 141-145 469 (13.0%) 1 (Reference) >145 3 (12.0%) 0.958 0.283 to 3.246 0.946

5 Lumbar (Model 3): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) 0.001 ≤135 35 (24.0%) 1.605 1.029 to 2.503 0.037 136-140 498 (12.5%) 0.936 0.805 to 1.089 0.391 141-145 469 (13.0%) 1 (Reference) >145 3 (12.0%) 0.462 0.06 to 3.58 0.46

Femoral Neck (Model 1): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) <0.001 ≤135 18 (12.3%) 3.206 1.907 to 5.391 <0.001 136-140 195 (4.9%) 1.169 0.941 to 1.453 0.159 141-145 151 (4.2%) 1 (Reference) >145 1 (4.0%) 0.95 0.128 to 7.069 0.96

Age >67 (N=8341) ≤135 96 (26.2%) 1.586 1.242 to 2.025 <0.001 136-140 661 (19.8%) 1.109 0.99 to 1.242 0.075 141-145 838 (18.3%) 1 (Reference) >145 7 (12.7%) 0.653 0.294 to 1.448 0.294 Femoral Neck (Model 2):

6 n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) <0.001 ≤135 18 (12.3%) 2.805 1.647 to 4.777 <0.001 136-140 195 (4.9%) 1.168 0.937 to 1.456 0.167 141-145 151 (4.2%) 1 (Reference) >145 1 (4.0%) 0.969 0.127 to 7.367 0.976

Neck (Model 3): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) 0.015 ≤135 18 (12.3%) 1.897 1.038 to 3.469 0.037 136-140 195 (4.9%) 1.168 0.918 to 1.486 0.206 141-145 151 (4.2%) 1 (Reference) >145 1 (4.0%) 1.325 0.163 to 10.803 0.793

Total Hip (Model 1): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium

7 Osteoporosis) interaction P Age <55 (N=7763) <0.001 ≤135 19 (13.0%) 4.018 2.406 to 6.713 <0.001 136-140 172 (4.3%) 1.208 0.957 to 1.524 0.112 141-145 129 (3.6%) 1 (Reference) >145 1 (4.0%) 1.119 0.15 to 8.337 0.912

Age 55-67 (N=8680) ≤135 21 (11.1%) 2.803 1.746 to 4.5 <0.001 136-140 181 (5.5%) 1.31 1.07 to 1.604 0.009 141-145 217 (4.2%) 1 (Reference) >145 2 (2.5%) 0.578 0.141 to 2.369 0.447

Age >67 (N=8341) ≤135 84 (22.9%) 2.254 1.738 to 2.922 <0.001 136-140 461 (13.8%) 1.22 1.068 to 1.394 0.003 141-145 534 (11.6%) 1 (Reference) >145 6 (10.9%) 0.93 0.396 to 2.181 0.867

Total Hip (Model 2): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P Age <55 (N=7763) <0.001 ≤135 19 (13.0%) 3.485 2.066 to 5.881 <0.001 136-140 172 (4.3%) 1.148 0.908 to 1.453 0.249 141-145 129 (3.6%) 1 (Reference) >145 1 (4.0%) 1.14 0.15 to 8.64 0.899

Age 55-67 (N=8680) ≤135 21 (11.1%) 2.671 1.66 to 4.297 <0.001 136-140 181 (5.5%) 1.278 1.043 to 1.567 0.018 141-145 217 (4.2%) 1 (Reference) >145 2 (2.5%) 0.589 0.144 to 2.413 0.462

Age >67 (N=8341) ≤135 84 (22.9%) 1.831 1.392 to 2.407 <0.001 136-140 461 (13.8%) 1.171 1.02 to 1.345 0.025 141-145 534 (11.6%) 1 (Reference) >145 6 (10.9%) 0.99 0.413 to 2.376 0.983

Total Hip (Model 3): n (% with Odds Ratio 95% Confidence Interval P Value Age-Sodium Osteoporosis) interaction P

8 Age <55 (N=7763) 0.002 ≤135 19 (13.0%) 2.464 1.362 to 4.458 0.003 136-140 172 (4.3%) 1.124 0.87 to 1.452 0.371 141-145 129 (3.6%) 1 (Reference) >145 1 (4.0%) 1.743 0.213 to 14.234 0.604

Model 1: Case mixed unadjusted model

Model 2: Adjusted for age, sex, and race

Model 3: Adjusted for model 2, plus BMI, serum albumin, calcium, glucose, medications, and comorbidities

9 Supplement Table 4:

Lumbar: n (% with Odds Ratio 95% Confidence Interval P Value Age-HI Osteoporosis) interaction P Age<55 (N=6740) <0.001 ≤3 924 (12.6%) 1 (Reference) 4-19 24 (14.5%) 0.933 0.582 to 1.494 0.772 20-104 31 (22.6%) 1.417 0.89 to 2.258 0.142 ≥105 26 (26.3%) 1.693 1.023 to 2.803 0.041

Age 55-67 (N=7204) ≤3 1575 (19.0%) 1 (Reference) 4-19 29 (20.9%) 1.314 0.844 to 2.047 0.227 20-104 29 (21.5%) 1.118 0.704 to 1.777 0.636 ≥105 18 (14.4%) 0.72 0.425 to 1.218 0.22

Age>67 (N=7193) ≤3 1981 (25.7%) 1 (Reference) 4-19 41 (26.1%) 1.053 0.708 to 1.564 0.8 20-104 56 (27.7%) 1.015 0.716 to 1.44 0.932 ≥105 96 (36.2%) 1.526 1.142 to 2.038 0.004 Femoral Neck: n (% with Odds Ratio 95% Confidence Interval P Value Age-HI Osteoporosis) interaction P Age<55 (N=6740) 0.029 ≤3 309 (4.2%) 1 (Reference) 4-19 22 (13.3%) 1.879 1.1 to 3.212 0.021 20-104 18 (13.1%) 1.64 0.904 to 2.976 0.103 ≥105 16 (16.2%) 2.019 1.076 to 3.789 0.029

Age>67 (N=7193) ≤3 1423 (18.4%) 1 (Reference) 4-19 43 (27.4%) 1.353 0.915 to 2.002 0.13 20-104 56 (27.7%) 1.245 0.875 to 1.772 0.223 ≥105 80 (30.2%) 1.223 0.898 to 1.666 0.202

Total Hip:

10 n (% with Odds Ratio 95% Confidence Interval P Value Age-HI Osteoporosis) interaction P Age<55 (N=6740) 0.001 ≤3 263 (3.6%) 1 (Reference) 4-19 22 (13.3%) 2.341 1.369 to 4.005 0.002 20-104 18 (13.1%) 2.178 1.197 to 3.963 0.011 ≥105 18 (18.2%) 3.573 1.944 to 6.566 <0.001

Age>67 (N=7193) ≤3 944 (12.2%) 1 (Reference) 4-19 31 (19.7%) 1.462 0.933 to 2.291 0.098 20-104 38 (18.8%) 1.12 0.733 to 1.71 0.601 ≥105 72 (27.2%) 1.741 1.251 to 2.423 0.001

HI: Hyponatremia Interval